GB1578748A

GB1578748A - 6-keterinimo-penicillins and their use as intermediates

Info

Publication number: GB1578748A
Application number: GB26720/76A
Authority: GB
Original assignee: Beecham Group PLC
Current assignee: Beecham Group PLC
Priority date: 1976-06-26
Filing date: 1976-06-26
Publication date: 1980-11-12
Also published as: NO772238L; BE856121A; ZA773849B; DE2728601A1; CA1080698A; SE8302353L; SE7707199L; ES470837A1; HU176476B; ATA449277A; SE438151B; AT361620B; NO780509L; CH636620A5; FR2370748B1; AU512826B2; US4182710A; NO780510L; SE8302353D0; FI771983A7

Description

PATENT SPECIFICATION ( 11) 1 578 748

X ( 21) Application No 26720/76 ( 22) Filed 26 Jun 1976 ( 19) ( 23) Complete Specification Filed 27 Jun 1977:

( 44) Complete Specification Published 12 Nov 1980 ( 51) INT CL 3, C 07 D 499/02 ( 52) Index at Acceptance C 2 C 1313 1510 200 214 215 220 226.

22 Y 246 247 250 254 256 25 Y 28 X 292 29 Y 30 Y 313 314 31 Y 328 332 338 339 33 Y -342 34 Y 351 352 355 364 366 367 368 36 Y 440 624 638 672 699 720 AA KE MG ( 72) Inventors: ANDREW WILLIAM TAYLOR GEORGE BURTON JOHN PETER CLAYTON ( 54) 6-KETENIMINO-PENCILLINS AND THEIR USE AS INTERMEDIATES ( 71) We, BEECHAM GROUP LIMITED, Beecham House, Great West Road, Brentford, Middlesex, England a British Company do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:

This invention relates to a class of intermediates' useful for the preparation of 5 antibactierially active penicillin derivatives, in particular 6 a-methoxy pencillins having a carboxylic acid function at the 2-position in the side-chain The invention also relates to a process for the preparation of the novel intermediates and to a process for their conversion to the penicillins.

British Patent Specification No 1,463,468 discloses a process for the preparation of 10

6-alkoxy pencillins which comprises reacting a 2 '-hydroxy or 2 '-halopenicillin with a halogenating agent to form a 2 ',3 '-dihaloimine and subsequently reacting this with an alkali metal alkoxide to give a 6-alkoxyketenimine which is hydrated to give the required product.

One disadvantage of this process is that the 2 '-hydroxy or 2 '-halopenicillin starting material must be prepared by acylation of 6-amino penicillanic acid with the corresponding 15 side-chain The process does not provide a method for the introduction of 6 a-alkoxy substituent directly into a 6-acylamino-penicillin.

Furthermore in the above process the 2 ',3 '-dihaloimine intermediate must be isolated in order to remove excess halogenating agent (such as phosphorus pentachloride) therefrom prior to treatment with the alkali metal alkoxide However in the case of a penicillin 20 derivative having a carboxylic acid function at the 2 '-position, the dihaloimine is thermally unstable and the process is therefore unsuitable for that class of penicillins The present invention is concerned with a process which enables 2 'carboxy acetamido penicillin derivatives to be converted into their 6 a-methoxy analogues The key intermediates for this process are novel ketenimines 25 Accordingly the present invention provides a ketenimine of formula ( 1):

H CH 3 -S R CC=N m m CH 3 30 C 02 R 1 CO 2 R 2 0 C 02 R 2 wherein R represents a furyl, thienyl, cycloalkyl, cycloalkenyl or phenyl group, or a phenyl 35 group mono-, di-, or tri-substituted with hydroxy, halogen, nitro, C-C 6, alkyl, C 1-C 6 alkoxy, amino or carboxy groups; Rl represents an ester-forming radical; and R 2 represents a carboxyl-blocking group.

Suitable groups R include 2 and 3 furyl, 2 and 3-thienyl, cyclopropyl, cyclobutyl, 40 1 578 748 cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexa-1, 4-dienyl, phenyl, 4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 3,4-hydroxyphenyl.

Most suitably R is 2 or 3-thienyl, phenyl or 4-hydroxyphenyl; preferably phenyl.

Suitable carboxyl blocking groups for R include in vivo hydrolysable ester forming radicals In vivo hydrolysable ester forming radicals are those which, when attached at that 5 position on a penicillin nucleus, hydrolyse in the human body to produce the parent acid It is well established that simple alkyl and aryl esters of penicillins fail to meet this requirement as they are resistant to hydrolysis by human tissues Examples of suitable in vivo hydrolysable ester radicals for the group R 2 include acyloxyalkyl groups such as acetoxymeth'yl, pivaloyloxymethyl, a-acetoxyethyl, cta-acetoxybenzyl and a 10 pivaloyloxyethyl groups; alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl and at-ethoxycarbonyloxyethyl; and lactone, thiolactone and dithiolactone groups, i e ester groups of formula:

-CO O -CH-Z' 15 -I=YI wherein X' and Y' are oxygen or sulphur and Z' is an ethylene group or a 1,2-phenylene 20 group optionally substituted by lower-alkoxy, halogen or nitro.

Preferred ester groups are the phthalide and 5,6-dimethoxyphthalide esters.

Other suitable carboxyl-blocking derivatives for the group R in formula (I), include salts, ester, and anhydride derivatives of the carboxylic acid The derivative should be one which may readily be cleaved at a later stage of the reaction Suitable salts include tertiary 25 amine salts, such as those with tri-C,_ 6 alkylamines N-ethyl-piperidine, 2,6-lutidine, pyridine, N-methylpyrrolidine, dimethylpiparazine A preferred salt is with triethylamine.

Suitable carboxyl-blocked groups or formula CO 2 R 2 include the following:

(i) -COOCRC Rd RC wherein at least one of R,, Rd and Re is an electrondonor e g.

p-methoxyphenyl, 2,4,6-trimethylphenyl, 9-anthryl, methoxy, acetoxy, 30 methoxymethyl benzyl or fur-2-yl The remaining R,, Rd and R, groups may be hydrogen or organic substituent groups Suitable ester groups of this type include p-methoxybenzyloxy-carbonyl, 2,4,6-trimethylbenzyloxy carbonyl, bis(p-methoxy-phenyl)methoxycarbonyl, 3,5-di-t-butyl-4-hydroxybenzyloxycarbonyl, methoxymethoxycarbonyl and benzyloxycarbonyl 35 (ii) -COOC Rc R Ro wherein at least one of Rc, R, and R, is an electionattracting group e g benzoyl, p-nitrophenyl, 4-pyridyl, trichloromethyl, tribromomethyl, iodomethyl, cyanomethyl, ethoxycarbonylmethyl, arylsulphonylmethyl, 2dimethylsulphoniumethyl, o-nitrophenyl or cyano The remaining Rc, Rd and 40, R, groups may be hydrogen or organic substitutent groups Suitable esters of 40 this type include benzoylmethoxycarbonyl, p-nitrobenzyloxycarbonyl,4pyridylmethoxycarbonyl, 2,2,2-trichloroethoxy-carbonyl and 2,2,2tribromoethoxycarbonyl.

(iii) -COOC Rc Rd RR wherein at least two of Rc, Rd and R, are hydrocarbons such as alkyl e g methyl or ethyl, aryl, e g phenyl and the remaining R,, Rd and R 45 groups, if there is one, are hydrogen Suitable esters of this type include t-butyl-oxycarbonyl, t-amyloxycarbonyl, diphenyl-methoxycarbonyl and triphenylmethoxycarbonyl.

(iv) -COOC Rf wherein Rf is adamantyl, 2-benzyloxy-phenyl, 4methylthiophenyl, tetrahydrofur-2-yl-tetrahydropyran-2-yl, pentachlorophenyl; 50 (v) Silyloxycarbonyl groups obtained by reaction of a silylating agent with the carboxylic acid group; (vi) COCP R,Rh, wherein R, is an alkyl, haloalkyl, aryl, aralkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy or dialkylamino group, Rb is the same as R, or is halogen or R, and Rh together form a ring 55 The carboxyl group may be regenerated from any of the above esters by usual methods for example, acid or base catalysed hydrolysis, or by enzymically catalysed hydrolysis.

Alternative methods of cleavage include:

reaction with Lewis acids, such as trifluoroacetic acid, formic acid, hydrochloric acid in acetic acid, zinc bromide in benzene and aqueous solutions or suspensions of mecuric 60 compounds (The reaction with the Lewis acid may be facilitated by addition of a nucleophile such as anisole); reduction with agents such as zinc/acetic acid, zinc/formic acid, zinc/lower alcohol, zinc/pyridine, palladised-charcoal and hydrogen, or sodium and liquid ammonia; attack by nucleophiles, such as those containing a nucleophilic oxygen or sulphur atom 65 3 1 578 748 for example alcohols, mercaptans and water; oxidative methods, for example, those which involve the use of hydrogen peroxide and acetic acid; and irradiation.

The group R' may be any ester-forming radical as hydrolysis to the free acid at that position is not essential for the activity of the eventually produced penicillin derivative The group R' may therefore be any of the carboxyl blocking ester groups described above 5 including those described as being in vivo hydrolysable when present at the 3-position of the penicillin nucleus.

Suitably the group R' may be an alkyl, cycloalkyl, alkenyl, alkynyl, aryl or heterocyclic group any of which may be substituted Such groups include:

(a) alkyl especially C,-6 alkyl such as methyl, ethyl, n and iso-propyl, n-, sec-, iso and 10 tert-butyl, and pentyl; (b) substituted C 1 _ 6 alkyl wherein the substituent is at least one of: chloro, bromo, fluoro, nitro, carbo (C 1 _ 6 alkoxy), C 1-6 alkanoyl, Cl 6 alkoxy, cyano, Cl_ 6 alkylthio, (C 1-6 alkylsulfinyl, C,_ 6 alkylsulphonyl, 1-indanyl, 2-indanyl, furyl, pyridyl, 4-imidazolyl, phthalimido, azetidino, aziridino, pyrrolidino, piperidino, morpholino, thiomorpholino, 15 N-(C 1-6 alkyl)piperazino, pyrrolo, imidazolo, 2-imidazolino, 2,5dimethylpyrrolidino, 1,4,5,6-tetrahydropyrimidino, 4-methylpiperidino, 2,6-dimethylpiperidino, alkylamino, dialkylamino, alkanoylamino, N-alkylanilino, or substituted N-alkylanilino wherein the substituent is chloro, bromo, C 1-6 alkyl or C 1-6 alkoxy; (c) cycloalkyl and (C 1-6 alkyl) substituted cycloalkyl having from 3 to 7 carbon atoms in the 20 cycloalkyl moiety; (d) alkenyl having up to 8 carbon atoms; (e) alkynyl having up to 8 carbon atoms; f) phenyl and substituted phenyl wherein the substituent is at least one of chloro, bromo, fluoro, Cl_ 6 alkoxy, Cl_ 6 alkanoyl, carbo-(C 116)alkoxy, nitro, or di(C 1 _ 6)alkyl amino; 25 (g) benzyl or substituted benzyl wherein the substituent is chloro, bromo, fluoro, Cl_ 6 alkyl, Ci-6 alkoxy, Cl 6 alkanoyl carbo(C 1,6)alkoxy, nitro, or di(C 1 _ 6) alkylamino; (h) groups such as: furyl, quinolyl, methyl-substituted quinolyl, phenazinyl, 1,3benzodioxolyl, 3-( 2-methyl)-y-pyronyl, 3-y-pyronyl or methylpyridyl; (i) groups such as: ac indanyl and substituted derivatives thereof wherein the substituent is 30 methyl, chloro or bromo; ac tetrahydronaphthyl and substituted derivatives thereof wherein the substituent is methyl, chloro or bromo; benzohydryl, trityl, cholesteryl, or bicyclol 4 4 O ldecyl.

Preferred groups for R' include C, 6 alkyl, benzyl, phthalidyl, indanyl, phenyl or mono-, -35 di-, and tri (Cl-C 6) alkyl substituted phenyl such as o-, m orp methylphenyl, ethylphenyl, 35 n or iso propylphenyl and n-, sec-, iso or t-butylphenyl.

The intermediates of formula (I) may be prepared by reacting a 6acylaminopenicillin of formula (II):

H 40 R.CH CO NH C C 02 R C 02 R 45 wherein R, R', and R 2 are as defined with respect to formula (I) above; with an acid halide.

Suitably the reaction with acid halide is carried out in the presence of an acid binding agent such as a tertary amine, e g pyridine, triethylamine or N,Ndimethylamine 50 Examples of suitable acid halides are phosphorus pentachloride, phosgene, phosphorous pentabromide, phosphorus oxychloride, oxalyl chloride and p-toluene sulphonic acid chloride Phosphorus pentachloride and phosphorus oxychloride are preferred The reaction may be conducted under cooling, preferably at temperatures from + 5 C to -30 C (preferably about O C) when phosphorus pentachloride is employed The amount of the 55 tertiary amine is preferably 3-5 mols per mol of phosphorus pentachloride It is also preferable to use the phosphorus halide in an amount in excess of that of the starting material.

The value of the ketenimine compounds of formula I derives from their use in the preparation of 6-methoxy penicillins 60 1 578 748 4 1 578 748 4 Thus in a further aspect, the present invention provides a process for preparing a compound of formula (III):

OCH 3 5 E S R.CH CO NH () I, N Co 2 R 3 C 02 R 4 10 wherein R is as defined above with respect to formula (I) above; R 3 represents hydrogen, a pharmaceutically acceptably salt forming ion or a pharmaceutically acceptable ester-forming radical; other than alkyl and R 4 represents hydrogen, a pharmaceutically acceptable salt-forming ion or in vivo 15 hydrolysable ester-forming radical; which process comprises:

(a) reacting a ketenimine of formula (I) with a double-bond addition reagent; (b) reacting the resulting product with a compound of formula CH 3 OM, wherein M is an alkali metal or thallium; (c) hydrolysing the resulting product; 20 (d) removing any carboxyl-blocking groups; and (e) optionally salifying or esterifying any free carboxylic acid group.

Suitable salt-forming ions for the groups R 3 and R 4 include metal ions e g aluminium, alkali metal ions such as sodium or potassium, alkaline earth metal ions such as calcium or magnesium, and ammonium or substituted ammonium ions for example those from Cl 6 25 alkylamines, such as triethylamine, hydroxy-lower alkylamines such as 2hydroxyethylamine, bis-( 2-hydroxyethyl)-amine or tri-( 2-hydroxyethyl)amine, cycloalkylamines such as dicyclohexylamine, or from procaine, dibenzylamine, N,Ndibenzylethylenediamine,'1-ephenamine, N-ethylpiperidine, N-benzyl-3phenethylamine, dehydroabietylamine, N,N'-bis-dehydroabietylethylenediamine, or bases of the pyridine 30 type such as pyridine, collidine or quinoline, or other amines which have been used to form salts with benzylpenicillin.

The double bond addition reagent is a difunctional moiety where each of the groups can be' displaced by nucleophiles.

' Suitable double bond addition reagents for the above process include diatomic halogen 35 molecules or a compound of formula Br N 3 If the double-bond addition reagent is designated X-Y, the adduct formed has the formula (IV):

x Y I' S 40 CO 2 R 1 C 2 R 2 45 Suitably both X and Y are halogen, preferably chlorine, as the reaction proceeds more smoothly.

The reaction is suitably carried out in an inert solvent, such as tetrahydrofuran or a halogenated hydrocarbon e g chloroform, at low temperatures such as + 20 C to -100 C 50 preferably -50 C to -80 C e g at about -70 C.

The compound of formula (IV) is then reacted with an alkali metal or thallium methoxide of formula CH 3 OM Suitably M may be sodium or potassium, but is preferably lithium The reaction is generally carried out in a polar solvent, preferably methanol, preferably in the presence of another inert solvent, such as tetrahydrofuran as long as it as it does not freeze 55 at the temperature of the reaction The reaction is suitably carried out at low temperature, preferably in the range -40 C to 80 C, preferably about -75 C The reagent CH 3 OM may be formed in situ by the use of methanol together with a base such as butyl lithium, lithium diisopropylamide, lithium or sodium hydride or preferably butyl lithium Preferably the steps (a) and (b) above are carried out without the isolation of the compound (IV) 60 1 578 _ 748 The thus produced 6 -methoxy ketenimine of formula (V):

OCH 3 S R-C-C-N 5 \ 5 I C "-'N ' (V) C 02 R 0/' -CO 2 R 2 10 is then hydrolysed.

Preferably this hydrolysis is carried out at a p H in the range 1 to 5 preferably p H 2 to 4, at ambient temperature Suitable solvents include tetrahydrofuran or acetone.

The following examples illustrate the preparation of a ketenimine intermediate of this invention and its use in preparing antibacterially active pencillins 15 "Carfecillin" is the pencillin of formula:

S Ph-CH-CO NH 20 I 20 CO 2 Ph C 2 H 25 EXAMPLE 1

Preparation of p-nitrobenzyl 6 ( 2 '-phenyl-2 ' -phenoxy-carbonyl) ketenimino penicillanate p-Nitrobenzyl 6 f-( 2 '-phenyl-2 '-phenoxycarbonyl)acetamido penicillanate ( 1 50 g, 2 54 mmol) in benzene ( 6 ml) was treated with pyridine ( 1 68 ml), added at O C Phosphorus 30 pentachloride ( 1 32 g, 6 36 mmol) in benzene ( 30 ml) was slowly added, with stirring at O C.

After three hours at O C, the solution was filtered The solids were washed with diethyl ether, and the combined organic layers washed successively with water and sodium bicarbonate solution, dried (Na SO 4) and evaporated to give almost pure title compound ( 1 23, 85 %), ltmax (CHC 13) 2030,1790,1740,1600,1530,1350 cm-' 8 (CDC 13) 1 36,1 42, 35 ( 6 H, 2 s, (CH 3)2 C), 4 56 ( 1 H,s,C 3-proton), 5 43 ( 2 H,s,-CH 2-), 5 77 ( 2 H,s,Cs and C 6-protons), 7 1-7 9 ( 12 H, complex, aryl protons), 8 37 ( 2 H,d,J 8 Hz, -CH-CNO 2-).

lHydrolysis of the title Ketenimine (aqueous T H F: phosphoric acid) at p H 4 over 24 hours, followed by addition of ethyl acetate, which was washed with water dried (Na 25 O 4) and evaporated, afforded starting p-nitrobenzyl 6 f 3-( 2 '-phenyl-2 ' 40 phenoxycarbonyl)acetamido penicillanate only with no trace of the 6 aepimer l EXAMPLE 2

Preparation of p-nitrobenzyl 6 a-methoxy-63-( 2 '-phenyl-2 'phenoxycarbonyl) ketenimino penicillanate 45 Method (i) (a) p-Nitrobenzyl-6 ( 1 ',2 ', dichloro-2 '-phenyl-2 ' -phenoxycarbonyl) ethylideneamino penicillanate The Ketenimine from example 1 ( 0 17 g, 0 3 mmol) in chloroform ( 3 ml) at -50 C was treated dropwise over 30 minutes with chlorine in chloroform until disappearance of max 50 (CHC 13) 2030 cm, concomitant with appearance of max (CHCI 3) 1670 cm-l After evaporation, the title product was obtained.

(b) p-Nitrobenzvl 6 ca-methoxy-6 ( 2 '-phenvl-2 '-phenoxycarbonyl) ketenimino penicillanate The imino chloride from (a) above was immediately used in (b) because of its instability 55 at room temperature Thus the imino chloride was dissolved in tetrahydrofuran (T H F) 2 ml) and this solution added to lithium methoxide ( 51 mig) in methanol (lml): T H F.

12 ml) at -75 C After stirring for twenty minutes, acetic acid ( 0 5 ml) was added, and the mixture warmed to room temperature Diethylether was added and washed with sodium bicarbonate solution and water, dried and evaporated to give a residue which was 60 chromatographed on silica (petrol/ethyl acetate), thus affording the desired title compound ( 0.045 g, 25 % for (a) and (b) overall), max (CHCI 3) 2030, 1790, 1730, 1600, 1530, 1500, 1350 cm-1 8 (CDCI 3) 1 28 ( 6 H,s,(CH 3)2 C), 3 58 ( 3 H,s,CH 30-), 4 33 ( 1 H,s,C 3-proton), 5.25 ( 2 H,s-CH Ar) 5 50 ( 1 H,s,C 5-proton), 7 1-7 6 ( 12 H complex, aryl protons), 8 15 ( 2 H,d,J 8 Hz,-CH-CNO 2-) 65 6 1578 7486 Method (ii) (This method avoids isolation of unstable intermediates) The Ketenimine from Example 1 ( 0 25 g, O 44 mmol) in T H F ( 15 ml) at 75 C was treated, with stirring, with bromine ( 0 024 ml 0 44 mmol) After 10 minutes, lithium methoxide ( 99 88 % purity) 65 mg) in methanol (lml) was added, dropwise After 10 minutes stirring at -75 C acetic acid ( O 5 ml) was added, and the reaction solution worked 5 up as in method (i) (b), thus affording the title compound ( 0 08 g 30 %).

EXAMPLE 3

Preparation of 2 '-epimers of p-nitrobenzyl 6 a-methoxy-6 fp-( 2 '-phenyl) -2 'phenoxycarbofiyl)acetamido penicillanate 10 Method (i) The Ketenimine from Example 2 ( 0 05 g) in T H F: H 20 ( 20; 1) (lml) was left at room temperature for 42 hours at p H 2 O (H 3 PO 4) Ethyl acetate was added, and the organic layer washed with water, dried and evaporated to give the title compound ( O 05 g), max (CHC 13) 3360, 1790, 1750, 1700, 1530, 1500, 1355 cm- 8 (CDCI 3) 1 23, 1 29 ( 6 H,2 S 15 (CH 3)2 C), 3 31, 3 36 ( 3 H,2 s,CH 30-), 4 29, 4 32 ( 1 H,2 s,C 3-proton) , 7 0-7 8 ( 13 H, complex, aryl and amide protons) 8 15 ( 2 H, d,J 8 Hz, -CH-CNO 2-).

Method (ii) The Ketenimine from Example 2 ( O O Sg) in aqueous acetone was stood at room 20 temperature for 42 hours at p H 3 1 (p-toluenesulphonic acid added to give the required acidity) Ethyl acetate was added, and the organic layer washed with sodium bicarbonate solution and water Drying and evaporation gave the title compound ( O 05 g).

EXAMPLE 4 25

Preparation of p-nitrobenzyl 63 ( 2 '( 3 "-thienyl)-2 '-pmethylphenoxycarbonyl)ketenimino penicillanate p-Nitrobenzyl 6 f-( 2 '-( 3 "-thienyl)-2 '-p-methylphenoxycarbonyl) acetamido penicillanate ( 3.57 g, 5 86 mmol) in benzene ( 18 ml) was treated dropwise at 5 with pyridine ( 4 29 ml) and subsequently with phosphorus pentachloride ( 3 72 g) in benzene ( 75 ml), at such a rate to 30 keep the temperature at 5 C After three hours stirring the solution was filtered, the solids washed with water and sodium bicarbonate solution Drying and evaporation gave the title compound ( 3 35 g, 97 %), max (CHCI 3) 2010, 1745, 1725, 1525, 1345 cm-I, 8 (CDCI 3) 1 38, 1.49 ( 6 H,2 s,(CH 3)2 C), 2 26 ( 3 H,s, CH 3 Ar), 4 38 ( 1 H,s, C 3proton), 5 25 ( 2 H,s,-OCH 2 Ar), 5 52 ( 2 H,s,C 5 and C 6 protons), 6 9-7 7 ( 9 H, complex, aryl and thienyl protons), 8 15 35 ( 2 H,d,J 8 Hz, -CH-CNO 2-).

EXAMPLE 5

Preparation of p-nitrobenzyl 6 a-methoxy-61-( 2 '-( 3 "-thienyl)-2 '-pmethylphenoxycarbonyl)Ketenimino penicillanate 40 Method 1 The Ketenimine from Example 4 ( 2 50 g, 4 21 mmol) in T H F ( 80 ml) at 70 was treated with chlorine ( 4 2 mmol), and the solution stirred for 20 minutes Lithium methoxide ( 0 44 g, 11 5 mmol) in methanol ( 12 ml) was added at such a rate ( 5 minutes) that the temperature stayed below -67 C After 10 minutes further, acetic acid ( 4 ml) was 45 added, and the solution was removed from the cooling bath Ethyl acetate was added, and the organic layer washed with sodium bicarbonate and brine, dried and evaporated to give the crude title compound ( 2 42 g) Purification is achieved by chromatography on silica (petrol/ethyl acetate), giving 40 % yield overall The title compound possesses max (CHC 13) 2010, 1790, 1750, 1725, 1525, 1345 cm-'l 8 (CDCI 3) 1 34 ( 6 H,s,(CH 3)2 C), 2 23 50 ( 3 H,s,CH 3 Ar), 3 58 ( 3 H,s,OCH 3), 4 36 ( 1 H,s,C 3-proton), 5 23 ( 2 H,s,-CH 2 Ar) 5 53 ( 1 H,s,C 5-proton), 6 8-7-7 ( 5 H, complex, aryl and thienyl protons, 8 16 ( 2 H,d,J 8 Hz,-CHCNO 2-).

Method 2 55 Substitution of sodium bicarbonate for lithium methoxide (molar proportions as method 1) as used in Method 1 gave the title compound in slightly lower yield than in Method 1.

Method 3 Substitution of bromine for chlorine (molar proportions as Method 1) as used in Method 60 1 gave the title compound in lower yield than in Method 1.

1 578 748 1 578 748 EXAMPLE 6 (a) Preparation of 2 '-epimers of p-nitrobenzyl 6 ac-methoxy-6 f 3-( 2 '( 3 "-thienyl)-2 '-pmethylphenoxycarbonyl)-acetamido penicillanate.

The Ketenimine from Example 5 ( 1 67 g, 2 69 mmol) was dissolved in T H F ( 30 ml) containing water (lml) and a few drops of H 3 PO 4 to lower the p H to 2 6 After three days 5 standing at room temperature, ethyl acetate was added, and washed with water Drying and evaporation gave the title compound ( 1 51 g, 88 %) max (CHC 13) 3350, 1790, 1750, 1700, 1525, 1350 cm-' 8 (CDCI 3) 1 29, 1 33 ( 6 H,2 s,(CH 3)2 C), 2 27 ( 3 H,s, CH 3 Ar), 3 33, 3 38 ( 3 H 2 s CH 30-), 4 31, 4 33 ( 1 H,2 s,C 3-proton), 4 87 ( 1 H,s,-CH-CON) , 5 28 ( 2 H,s,OCH 2 Ar), 5 57 ( 1 H,s,Cs-proton), 6 8-7 6 ( 1 OH, complex, aryl, thienyl and amide protons), 10 8.17 ( 2 H,d,J 8 Hz, -CH-CNO 2-) (b) 2 '-epimers of 6 ax-methoxy-6 j,-( 2 '( 3 "-thienyl)-2 '-pmethylphenoxycarbonyl)acetamido penicillanic acid.

The p-nitrobenzyl ester from (a) above ( 1 O g, 2 59 mmol) in ethanol ( 15 ml): T J F 15 ( 4 ml): water (a few drops) was hydrogenated over Pd/C ( 10 %; lg) for four hours The solution was filtered the solids washed with acetone, and the combined solutions evaporated to give the title compound and hydrogenolysed p-toluidene (total weight, 0.89 g) The latter material was removed by precipitation of the penicillin as the sodium salt from acetone; diethyl ether with sodium 2-ethyl hexanoate in methyl isobutyl ketone ( 2 N, 20 0.73 ml) (Overall yield from ester: 76 %).

(c) 2 '-epimers of 6 a-methoxy-6 f-( 2 '( 3 "-thienyl)-2 'carboxyacetamido)penicillanic acid The monoester from (b) above ( 5 66 g, 10 5 mmol) in water ( 20 ml) was stirred for 2 hours with Na 2 B 407 decahydrate ( 8 2 g) The p H was adjusted to 4, and the solution washed with 25 ethyl acetate.

The p H was then lowered to 2, and the solution extracted with ethyl acetate Drying and evaporation gave the title compound ( 3 5 g) which was precipitated as the di-sodium salt from acetone with sodium 2-ethyl hexanoate in methyl isobutyl ketone ( 2 N, 9 O ml).

(Overall yield from ester: 74 %) The di-sodium salt possess max (nujol Registered Trade 30 Mark) 1760, 1670, 1600 cm-l, 8 (D 20) 1 44 ( 6 H,s,(CH 3)2 C), 3 51, 3 60 ( 3 H,2 s,-OCH 3), 4.34 ( 1 H,s,C 3-proton), 5 61 ( 1 H,s,C 5-proton, 7 1-7 7 ( 3 H, complex, thienyl protons).

EXAMPLE 7

Preparation of p-bromophenacyl 6,-( 2 '( 3 "-thienyl)-2 '-pmethylphenoxycarbonyl) 35 ketenimino penicillanate.

p-Bromophenacyl 6 (-( 2 ' -( 3 "-thienyl)-2 '-p-methylphenoxy-carbonyl) acetamido penicillanate ( 0 89 g, 1 33 mmol) in benzene ( 5 ml) was treated successively at 5 o C with pyridine ( 1.02 ml) and phosphorus pentachloride ( 0 84 g) in benzene ( 20 ml) After stirring for three hours, solids were filtered and washed with ethyl acetate, and the organic solution washed 40 with water, sodium bicarbonate and brine Drying and evaporation gave the title compound ( 0.87 g, 95 %) max (CHCI 3) 2040, 1790, 1750, 1700 cm-' 8 (CDC 13) 1 64, 1 67 ( 6 H,2 s,(CH 3)2 C), 2 33 ( 3 H,s,CH 3 Ar), 4 64 ( 1 H,s,C 3-proton), 5 37 ( 2 H,A Bq,J 17 Hz, -OCH 2 CO Ar) 5 64 ( 2 H,s,C 6-protons), 7 0-7 9 ( 11 H, complex, thienyl and aryl protons).

45 EXAMPLE 8

Preparation of p-bromophenacyl 6 ct-methoxy-6 O-( 2 '-( 3 "-thienyl)-2 'p-methylphenoxycarbonyl)ketenimino penicillanate.

Method 1 The Ketenimine from Example 7 ( 0 32 g, 0 54 mmol) in T H F (l Oml) at 70 C was 50 treated with chlorine ( 0 54 mmol) and stirred for 10 minutes Sodium methoxide in methanol ( 1 M solution, 1 5 ml) was added, and the solution stirred for a further 10 minutes at -70 Acetic acid ( 0 5 ml) was added, followed by ethyl acetate, and the organic solution was washed with sodium bicarbonate solution and brine to give the crude title compound ( 0 32 g) Purified material was obtained by chromatgraphy on silica (petrol/ethyl acetate) 55 The title compound possesses max (CHCI 3) 2040, 1790, 1750, 1700 cm-1 8 (CDCI 3) 1 52, 1.66 ( 6 H,s,(CH 3)2 C), 2 38 ( 3 H,s,CH 3 Ar, 3 78 ( 3 H,s,-OCH 3), 4 68 ( 1 H,s C 3-proton), 5 48 ( 2 H,s,-OCH 2 CO Ar), 5 68 ( 1 H,s,C 5-proton,), 7 1-8 0 ( 11 H, complex, thienyl and aryl protons).

60 Method 2 Substitution of bromine for chlorine as used in Method 1 (molar proportions as in 1) gave a lower yield of title compound than Method 1.

8 1 578 748 Method 3 Substitution of lithium methoxide for sodium methoxide, and bromine for chlorine as used Method 1 (molar proportions as in 1) gave a lower yield of title compound than Method 1.

5 Method 4 The Ketenimine from Example 7 ( 0 25 g, 0 42 mmol) in T H F ( 2 ml) at 70 was treated with bromine ( 0 023 ml, 0 42 mmol) After 10 minutes the T H F solution was mixed with thallium (I) methoxide ( 1 lmmol) suspension in methanol (lml) pre-cooled to -50 C, and the mixture vigorously stirred for 30 minutes at-50 Acetic acid ( 0 5 ml) was then added, 10 the precipitate filtered and ethyl acetate added Washing with sodium bicarbonate solution and water, drying and evaporation gave the crude title compound ( 0 22 g) in slightly lower purity than in Method 1.

EXAMPLE 9 15 (a) Preparation of 2 '-epimers of p-bromophenacyl 6 ct-methoxy-63-( 2 '-( 3 "-thienyl)-2 'pmethylphenoxycarbonyl)acetamido penicillanate The purified Ketenimine from Example 8 ( 0 30 g, O 44 mmol) was dissolved in T H F.

(Sml) containing water ( 0 2 ml) and phosphoric acid, sufficient to lower the p H to 2 6 After three days at room temperature, ethyl acetate was added, and washed with water Drying 20 and evaporation gave the title compound ( 0 26 g, 84 %) max (CH C 13), 3350, 1780, 1760, 1750, 1690 cm-t 8 (CDCI 3), 1 40, 1 60 ( 6 H,2 s,(CH 3)2 C), 2 34 ( 3 H,s, CH 3 Ar), 3 45, 3 49 ( 3 H,2 s,CH 30-), 4 61 ( 1 H,s,C 3-proton), 5 16 ( 1 H,s,-CH-CON), 5 44 ( 2 H,s,OCH 2 CO 2 Ar) 5 71 ( 1 H,s,Cs-proton), 6 9-8 1 ( 12 H, complex, thienyl, aryl, and amide protons) 25 (b) Preparation of 2 'epimers of 6 cx-methoxy-613-( 2 '-( 3 "-thienyl)-2 '-pmethylphenoxycarbonyl)acetamido penicillanic acid.

Method 1 The p-bromophenacyl ester from (a) above ( 0 26 g) in dimethylformamide ( 6 ml): acetic 30 acid ( 3 ml) was stirred with zinc dust ( 0 7 g) for 75 minutes at room temperature The solution was filtered and solids washed with ethyl acetate The organic layer was washedwith water and extracted with sodium bicarbonate solution The aqueous layer was acidified to p H 1 8 and extracted with ethyl acetate Drying and evaporation gave the title compound ( 40 mg) max (CHC 13) 3400-2400 (br), 1775, 1740, 1695 cm-1 8 (CD C 13) 1 39, 1 51 35 ( 6 H,2 s,(CH 3)2 C), 2 38 ( 3 H,s,CH 3 Ar), 3 50 ( 3 H,s,-OCH 3), 4 47 ( 1 H,s,C 3-proton), 5 10 ( 1 H,s,-CH-CON), 5 67 ( 1 H,s,C 5-proton),7 0-8 2 ( 9 H, complex, thienyl, aryl, acid and amide protons).

(c) The 2 '-epimers of 6 ac-methoxy-6-3-( 2 '-( 3 "-thienyl)-2 '-carboxy) acetamido penicillanic 40 acid were prepared as described in Example 6 (c).

EXAMPLE 10

Preparation of p-bromnophenacyl 6 f 3-( 2 ' -benzyloxycarbonyl-2 ' ( 3 "thienyl)ketenimino penicillanate 45 p-Bromophenacyl 613-( 2 '-benzyloxycarbonyl-2 '-( 3 "-thienyl))-acetamido penicillanate ( 0.89 g, 1 33 mmol) in benzene ( 5 ml) was treated dropwise at 5 with pyridine ( 1 02 ml), and subsequently with phosphorus pentachloride ( 0 84 g) in benzene ( 20 ml), at such a rate to keep the temperature at 5 C After three hours stirring, the solution was filtered the solids washed with ethyl acetate, and the organic solution washed with water and sodium 50 bicarbonate solution Treatment with charcoal, drying and evaporation gave the title compound ( 0 70 g, 76 %) max (CHC 13) 2030, 1790, 1760, 1750 cm 8 (CD C 13) 1 59, 1 63, ( 6 H,2 s,(CH 3)2 C), 4 59 ( 1 H,s,C 3-proton), 5 28 ( 2 H,s,-CH 2 Ph), 5 39 ( 2 H,AB 3 q, J 17 Hz, -CH 2 CO Ar), 5 55 ( 2 H,A Bq, J 4 Hz, C 5 and C 6 protons), 6 9-7 7 ( 12 H, complex, aryl and thienyl protons) 55 EXAMPLE 11

Preparation of p-bromophenacyl 6 ( 2 '-o-isopropylphenoxycarbonyl-2 ' ( 3 "-thienyl))Ketenimino penicillanate.

p-Bromophenacyl 613-( 2 '-o-isopropylphenoxycarbonyl-2 '-( 3 "-thienyl)) acetamido penicil 60 lanate)0 44 g, 0 63 mmol) in benzene ( 3 ml) was treated with pyridine ( 0 48 ml) and phosphorus pentachloride ( 0 40 g) in benzene (l Oml) under the same conditions as used in Example 10 Work up as in Example 10 gave title compound ( 0 35, 82 %) max (CH C 13) 2000, 1785, 1750, 1700 cm 8 (CDC 13) 1 21 ( 6 H d,J 7 Hz, (CH 3)2 CH), 1 65 ( 6 H,s,(CH 3)2 C), 3 05, sept, J 7 Hz, -CH Me 2), 4 63 ( 1 H,s,C 3proton) 5 44 ( 2 H,A Bq,J 65 1 578 748 1 578 748 17 Hz, -CH 2 CO Ar), 5 65 ( 2 H,s,C 5 and C 6-protons), 7 1-8 O ( 1 H, complex, thienyl and aryl protons).

EXAMPLE 12

Preparation of p-bromophenacyl 613-( 2 '-methoxycarbonyl-2 '-( 3 "thientyl))Ketenimino peni 5 cillanate.

p-Bromophenacyl 613-( 2 'methoxycarbonyl-2 '-( 3 "-thienyl))acetamido penicillanate ( 0.49 g O X 2 mmol) in benzene (Sml) was treated with pyridine ( 0 63 ml) and phosphorus pentachloride ( O 52 g) in benzene ( 15 ml) under the same conditions as used in Example 10.

Work up as in Example 10 gave the title compound ( 0 35 g, 74 %) max(CHCI 3) 2000, 1780, 10 1750, 1700 cm-1 8 (CDCI 3) 1 67 ( 6 H,s,(CH 3)2 C), 3 69 ( 3 H,s,-OCH 3), 4 67 (IH s,C 3proton), 5 45 ( 2 H,A Bq, J 18 Hz, -CH 2 CO Ar), 5 66 ( 2 H A Bq, superimposed as "t", "J" Hz, C 5 and C 6,-protons), 7 0-8 O ( 7 H complex, thienyl and aryl protons).

Claims

WHAT WE CLAIM IS:

1 A ketenimine, having the formula (I): 15 H CH E R C-C=N, C 3 l 20 C 02 R 1 N-\ 0 O Ry N C 02 R 2 wherein R represents a furyl thienyl, cycloalkyl cycloalkenyl, or phenyl group, or a phenyl group mono-, di-, or tri-substituted with hydroxy, halogen nitro, C, C 6 alkyl Cl-C 6 25 alkoxy, amino or carboxy groups:

R' represents an ester-forming radical: and R 2 represents a carboxy-blocking group.

2 A ketenimine as claimed in claim I wherein R is 2 or 3 thienyl phenyl or 4-hydroxyphenvl 30 3 A ketenimine as claimed in claim 2 wherein R is phenyl.

4 A ketenimine as claimed in claim 2 wherein R is 3-thienyl.

A ketenimine as claimed in any one of claims 1 to 4 wherein R' is C 1, alkyl benzyl, phthalidyl, indanyl phenyl, or mono-, di- or tri-(C,16)alkvl substituted phenvl.

6 A process for the preparation of a compound as claimed in claim I which process 35 comprises reacting a 6-acylaminppenicillin of formula (II):

_H CH 3 S -R CH CO NH 1 -( CH 3 40 C 02 R 1 C 02 R 2 45 wherein R R' and R are as defined in claim 1: with an acid halide.

7 A process as claimed in claim 6 wherein the acid halide is phosphorus pentachloride, phosgene phosphorus pentabromide phosphorus oxychloride oxalyl chloride or ptoluenesulphonic acid chloride.

8 A process as claimed in either claim 6 or 7 which process is carried out in the 50 presence of a tertiary amine.

9 A 6 ac-methoxv ketenimine of formula (V):

9 OCH 3 CH 3 55 S R-C=C=N CH 3 C 02 R' C 02 R 60 wherein R and R 2 are as defined in claim I and R' represents an esterforming radical other than alkvl.

A ketenimine as claimed in claim 9 wherein R is 2 or 3-thienyl phenyl or 4-hvdroxvphenvl 65 1 578 748 11 A ketenimine as claimed in claim 10 wherein R is phenyl 12 A ketenimine as claimed in claim 10 wherein R is 3-thienyl.

13 A ketenimine as claimed in any one of claims 9 to 12 wherein R' is benzyl, phthalidyl, indanyl, phenyl, or mono-, di-, or tri-(C 1 _ 6)alkyl substituted phenyl.

14 A process for the preparation of a compound of formula (III): 5 QCH 3 CH 3 R CHCO NH CH 3 10 01,0 CO 2 R 3 C 02 R 4 wherein R is as defined in claim 1; 15 R 3 represents hydrogen, a pharmaceutically acceptable salt-forming ion or a pharmaceutically acceptable ester forming radical other than alkyl; and R 4 represents hydrogen, a pharmaceutically acceptable salt-forming ion or an in vivo hydrolysable ester-forming radical; which process comprises:

(i) hydrolysing a 6 a-methoxy ketenimine of formula (V) as claimed in claim 9; 20 (ii) removing any carboxyl-blocking groups; and (iii) optionally salifying or esterifying any free carboxylic acid group.

A process as claimed in claim 14 wherein the hydrolysis is carried out at a p H of from 2 to 4.

16 A process as claimed in either claim 14 or 15 wherein the 6 a-methoxy ketenimine of 25 formula (V) is prepared by reacting a compound of formula (IV):

-i I Sc 30 R_ -R S CH 3 02 RR C 02 R 1 '::OR 2 35 wherein R, R' and R 2 are as defined in claim 9 and X and Y are the radicals of a double-bond addition reagent; with a compound of formula CH 3 OM wherein M is an alkali metal or thallium.

17 A process as claimed in claim 16 wherein X and Y both represent halogen 40 18 A process as claimed in claim 17 wherein X and Y both represent chlorine.

19 A process as claimed in any one of claims 16 to 18 which is carried out without the isolation of the compound of formula (IV).

A process for preparation of a 6 act-methoxyketenimine as claimed in claim 9, which process comprises reacting a compound of formula (IV) as defined in claim 16 with a 45 compound of formula CH 3 OM wherein M is an alkali metal or thallium.

21 A process for the preparation of a compound of formula (V).

O 9 CH 3 CH 3 50 so R-CC=N CH 3 wh iR a Cno 2 R' o//d -CO 2 R 25 55 wherein R, R' and R 2 are as defined in claim 9 which process comprises:

(a) reacting a ketenimine as claimed in claim 1 with a double bond addition reagent; and (b) reacting the resulting product with a compound of formula CH 3 OM, wherein M is an alkali metal or thallium 60 22 A process as claimed in claim 21 which is carried out without isolating the intermediate produced in step (a).

23 A process as claimed in either claim 21 or 22 wherein the double bond addition reagent is chlorine.

1 578 748 24 A process for the preparation of a compound of formula (III):

O QCH 3 CH 3 s R CH CO NH r C CH 3 I I-N C 02 R 3 o CO 2 R 4 10 wherein R is as defined in claim 1, R 4 is as defined in claim 14, and R 3 represents hydrogen, a pharmaceutically acceptable salt-forming ion or ester forming radical; which process comprises:

(a) reacting a ketenimine as claimed in claim 1 with a double bond addition reagent; 15 (b) reacting the resulting product with a compound of formula CH 3 OM, wherein M is an alkali metal or thallium; (c) hydrolysing the resulting product; (d) removing any carboxyl-blocking groups; and (e) optionally salifying or esterifying any free carboxylic acid group 20 A process as claimed in claim 24 which is carried out without isolating the intermediate produced in step (a).

26 A process as claimed in either of claims 24 or 25 wherein the double bond reagent is chlorine.

27 p-Nitrobenzyl 6 l-( 2 '-phenyl-2 '-phenoxycarbonyl) ketenimino penicillanate 25 28 p-Nitrobenzyl 6 j 3-( 2 '-( 3 "-thienyl)-2 '-p-methyl-phenoxycarbonyl) ketenimino penicillanate.

29 p-Bromophenacyl 6 f-( 2 '-( 3 "-thienyl)-2 '-p-methylphenoxycarbonyl) ketenimino penicillanate.

30 p-Bromophenacyl 6 f-( 2 '-benzyloxycarbonyl-2 '-( 3 "-thienyl) ketenimino penicil 30 lanate.

31 p-Bromophenacyl 63-( 2 '-o-isopropylphenoxycarbonyl-2 '-( 3 "-thienyl) ketenimino penicillanate.

32 p-Bromophenacyl 63-( 2 '-methoxycarbonyl-2 '-( 3 "-thienyl))ketenimino penicillanate 35 33 A process as claimed in claim 6 substantially as hereinbefore described with reference to any one of Examples 1,4,7,10,11 or 12.

34 A process as claimed in 14 substantially as hereinbefore described with reference to any one of Examples 3,6 or 9.

35 A process as claimed in claim 21 or 22 substantially as hereinbefore described with 40 reference to any one of Examples 2,5 or 8.

A HESKETT, Chartered Patent Agent, Agent for the Applicants 45 Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited, Croydon, Surrey, 1980.

Published by The Patent Office, 25 Southampton Buildings, London, WC 2 A l AY,from which copies may be obtained.